RUNX1

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RUNX1
PDB 1cmo EBI.jpg
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1CMO, 1CO1, 1E50, 1H9D, 1LJM

Identifikatori
AliasiRUNX1
Vanjski ID-jeviOMIM: 151385 MGI: 99852 HomoloGene: 1331 GeneCards: RUNX1
Lokacija gena (čovjek)
Hromosom 21 (čovjek)
Hrom.Hromosom 21 (čovjek)[1]
Hromosom 21 (čovjek)
Genomska lokacija za RUNX1
Genomska lokacija za RUNX1
Bend21q22.12Početak34,787,801 bp[1]
Kraj36,004,667 bp[1]
Lokacija gena (miš)
Hromosom 16 (miš)
Hrom.Hromosom 16 (miš)[2]
Hromosom 16 (miš)
Genomska lokacija za RUNX1
Genomska lokacija za RUNX1
Bend16 C4|16 53.7 cMPočetak92,398,354 bp[2]
Kraj92,623,037 bp[2]
Obrazac RNK ekspresije
PBB GE RUNX1 209359 x at fs.png

PBB GE RUNX1 209360 s at fs.png

PBB GE RUNX1 208129 x at fs.png
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija DNA binding
calcium ion binding
RNA polymerase II transcription regulatory region sequence-specific DNA binding
protein homodimerization activity
GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity
GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific
transcription factor binding
GO:0001948, GO:0016582 protein binding
protein heterodimerization activity
ATP binding
GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding
Ćelijska komponenta intracellular membrane-bounded organelle
Jedro
citosol
Nukleoplazma
core-binding factor complex
Biološki proces peripheral nervous system neuron development
myeloid cell differentiation
GO:0009373 regulation of transcription, DNA-templated
chondrocyte differentiation
ossification
negative regulation of granulocyte differentiation
hematopoietic stem cell proliferation
transcription, DNA-templated
positive regulation of angiogenesis
GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
positive regulation of interleukin-2 production
positive regulation of granulocyte differentiation
GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
transcription by RNA polymerase II
regulation of cytokine-mediated signaling pathway
regulation of Wnt signaling pathway
regulation of intracellular estrogen receptor signaling pathway
regulation of regulatory T cell differentiation
regulation of keratinocyte differentiation
regulation of myeloid cell differentiation
regulation of megakaryocyte differentiation
regulation of B cell receptor signaling pathway
regulation of hematopoietic stem cell differentiation
regulation of bicellular tight junction assembly
Hematopoeza
GO:1901227 negative regulation of transcription by RNA polymerase II
negative regulation of CD4-positive, alpha-beta T cell differentiation
positive regulation of CD8-positive, alpha-beta T cell differentiation
negative regulation of gene expression
neuron differentiation
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_001001890
NM_001122607
NM_001754

NM_001111021
NM_001111022
NM_001111023
NM_009821

RefSeq (bjelančevina)

NP_001001890
NP_001116079
NP_001745

n/a

Lokacija (UCSC)Chr 21: 34.79 – 36 MbChr 16: 92.4 – 92.62 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Runt-srodni transkripcijski faktor 1 (RUNX1), znan i kao protein 1 akutne mijeloidne leukemije (AML1) ili podjedinica alfa-2 jezgarno vezanog faktora (CBFA2) jest protein koji je kod ljudi kodiran genom RUNX1 sa hromosoma 21.[5][6]

Aminokiselinska sekvenca[uredi | uredi izvor]

Dužina polipeptidnog lanca je 453 aminokiseline, a molekulska težina 48.737 Da.[6]

1020304050
MRIPVDASTSRRFTPPSTALSPGKMSEALPLGAPDAGAALAGKLRSGDRS
MVEVLADHPGELVRTDSPNFLCSVLPTHWRCNKTLPIAFKVVALGDVPDG
TLVTVMAGNDENYSAELRNATAAMKNQVARFNDLRFVGRSGRGKSFTLTI
TVFTNPPQVATYHRAIKITVDGPREPRRHRQKLDDQTKPGSLSFSERLSE
LEQLRRTAMRVSPHHPAPTPNPRASLNHSTAFNPQPQSQMQDTRQIQPSP
PWSYDQSYQYLGSIASPSVHPATPISPGRASGMTTLSAELSSRLSTAPDL
TAFSDPRQFPALPSISDPRMHYPGAFTYSPTPVTSGIGIGMSAMGSATRY
HTYLPPPYPGSSQAQGGPFQASSPSYHLYYGASAGSYQFSMVGGERSPPR
ILPPCTNASTGSALLNPSLPNQSDVVEAEGSHSNSPTNMAPSARLEEAVW
RPY

Gen i protein[uredi | uredi izvor]

Kod ljudi, gen RUNX1 je dug 260 kilobaza (kb) i nalazi se na hromosomu 21 (21q22.12). Gen se može transkribirati preko dva alternativna promotora, promotor 1 (distalni) ili promotor 2 (proksimalni). Kao rezultat, različite izoforme runx1 mogu biti sintetizovane, što je olakšano alternativnom preradom. RUNX1 protein pune dužine kodiran je sa 12 egzona. Među egzonima su dva definirana domena, domen homologije runt (RHD) ili runt domen (egzoni 2, 3 i 4) i domen transaktivacije (TAD) (egzon 6). Ovi domeni su neophodni da RUNX1 posreduje u vezivanju DNK i interakciji protein-protein. Transkripciju RUNX1 reguliraju dva pojačivača (regulatorni element 1 i regulatorni element 2), a ovi tkivno specifični pojačivači omogućavaju vezivanje limfoidnih ili eritroidnih regulatornih proteina; stoga je genska aktivnost RUNX1 visoko aktivana u hematopoetskom sistemu.

Protein RUNX1 sastoji se od 453 aminokiseline. Kao faktor transkripcije (TF), njegova sposobnost vezivanja za DNK je kodirana runt domenom (ostaci 50 – 177), koji je homologan porodici p53. Runt domen RUNX1 se veže za osnovnu konsenzusnu sekvencu TGTGGNNN (gde NNN može predstavljati ili TTT ili TCA).[7] Prepoznavanje DNK postiže se petljama 12-lančanog β-barela i C-terminalnog "repa" (ostaci 170 – 177), koji se stežu oko kičme šećernog fosfata i uklapaju se u glavne i male spirale DNK. Specifičnost se postiže direktnim ili vodenim kontaktima sa bazama. RUNX1 može da veže DNK kao monomer, ali njegov afinitet vezivanja za DNK povećava se 10 puta ako se heterodimerizuje sa faktorom vezivanja jezgra β (CBFβ), također preko runt domena. U stvari, porodica RUNX naziva se često α-podjedinicama, zajedno sa vezivanjem zajedničke β-podjedinice CBFβ, RUNX se može ponašati kao heterodimerni faktori transkripcije koji se zajednički nazivaju jezgarno vezujući faktori (CBFs).

Utvrđeno je da je konsenzusno vezujuće mjesto za CBF sekvenca od 7 bp PyGPyGGTPy. Py označava pirimidin koji može biti ili citozin ili timin.[8]

Funkcija[uredi | uredi izvor]

RUNX1 je transkripcijski faktor koji reguliše diferencijaciju hematopoetskih matičnih ćelija u zrele krvne ćelije.[9] Osim toga, ima važnu ulogu u razvoju neurona koji prenose osjećaj boli.[10] Pripada porodici gena vezanih za transkripcijski faktor (RUNX) koji se takođe nazivaju faktori jezgarnog vezivanja-α (CBFα). RUNX proteini formiraju heterodimerni proteinski kompleks sa CBFβ koji omogućava povećano vezivanje DNK i stabilnost kompleksa.

Klinički značaj[uredi | uredi izvor]

Hromosomske translokacije koje uključuju gen RUNX1 povezane su s nekoliko tipova leukemija uključujući akutnu mijeloblastnu leukemiju sa sazrijevanjem]] (M2 AML).[11] Mutacije u RUNX1 upletene su u slučajeve raka dojke.[12]

Interakcije[uredi | uredi izvor]

Pokazano je da RUNX1 reaguje sa:

Također pogledajte[uredi | uredi izvor]

Reference[uredi | uredi izvor]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000159216 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022952 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: RUNX1 runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)".
  6. ^ a b Avramopoulos D, Cox T, Blaschak JE, Chakravarti A, Antonarakis SE (October 1992). "Linkage mapping of the AML1 gene on human chromosome 21 using a DNA polymorphism in the 3' untranslated region". Genomics. 14 (2): 506–7. doi:10.1016/S0888-7543(05)80253-8. PMID 1427868.
  7. ^ Bowers SR, Calero-Nieto FJ, Valeaux S, Fernandez-Fuentes N, Cockerill PN (October 2010). "Runx1 binds as a dimeric complex to overlapping Runx1 sites within a palindromic element in the human GM-CSF enhancer". Nucleic Acids Research. 38 (18): 6124–34. doi:10.1093/nar/gkq356. PMC 2952845. PMID 20483917.
  8. ^ Melnikova IN, Crute BE, Wang S, Speck NA (April 1993). "Sequence specificity of the core-binding factor". Journal of Virology. 67 (4): 2408–11. doi:10.1128/JVI.67.4.2408-2411.1993. PMC 240414. PMID 8445737.
  9. ^ Okuda T, Nishimura M, Nakao M, Fujita Y (October 2001). "RUNX1/AML1: a central player in hematopoiesis". International Journal of Hematology. 74 (3): 252–7. doi:10.1007/bf02982057. PMID 11721959. S2CID 5918511.
  10. ^ Chen CL, Broom DC, Liu Y, de Nooij JC, Li Z, Cen C, Samad OA, Jessell TM, Woolf CJ, Ma Q (February 2006). "Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain". Neuron. 49 (3): 365–77. doi:10.1016/j.neuron.2005.10.036. PMID 16446141. S2CID 16070223.
  11. ^ Asou N (February 2003). "The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications". Critical Reviews in Oncology/Hematology. 45 (2): 129–50. doi:10.1016/S1040-8428(02)00003-3. PMID 12604126.
  12. ^ Koboldt DC (October 2012). "Comprehensive molecular portraits of human breast tumours". Nature. Nature Publishing Group. 490 (7418): 61–70. Bibcode:2012Natur.490...61T. doi:10.1038/nature11412. PMC 3465532. PMID 23000897.
  13. ^ a b Hess J, Porte D, Munz C, Angel P (June 2001). "AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element". The Journal of Biological Chemistry. 276 (23): 20029–38. doi:10.1074/jbc.M010601200. PMID 11274169.
  14. ^ a b D'Alonzo RC, Selvamurugan N, Karsenty G, Partridge NC (January 2002). "Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation". The Journal of Biological Chemistry. 277 (1): 816–22. doi:10.1074/jbc.M107082200. PMID 11641401.
  15. ^ Chakraborty S, Sinha KK, Senyuk V, Nucifora G (August 2003). "SUV39H1 interacts with AML1 and abrogates AML1 transactivity. AML1 is methylated in vivo". Oncogene. 22 (34): 5229–37. doi:10.1038/sj.onc.1206600. PMID 12917624.
  16. ^ Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y (September 1998). "Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors". Proceedings of the National Academy of Sciences of the United States of America. 95 (20): 11590–5. Bibcode:1998PNAS...9511590L. doi:10.1073/pnas.95.20.11590. PMC 21685. PMID 9751710.
  17. ^ a b Puccetti E, Obradovic D, Beissert T, Bianchini A, Washburn B, Chiaradonna F, Boehrer S, Hoelzer D, Ottmann OG, Pelicci PG, Nervi C, Ruthardt M (December 2002). "AML-associated translocation products block vitamin D(3)-induced differentiation by sequestering the vitamin D(3) receptor". Cancer Research. 62 (23): 7050–8. PMID 12460926.

Dopunska literatura[uredi | uredi izvor]

Vanjsi linkovi[uredi | uredi izvor]